rs876658502
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.3085dupA(p.Thr1029AsnfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.3085dupA | p.Thr1029AsnfsTer19 | frameshift_variant | Exon 21 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459460Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726260
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74364
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:3
- -
Variant summary: ATM c.3085dupA (p.Thr1029AsnfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3245_3247delinsTGAT (p.His1082fsX14), c.3712_3716delTTATT (p.Leu1238fsX6)). The variant was absent in 246070 control chromosomes (gnomAD) but has been reported in the literature in multiple compound heterozygous individuals affected with Ataxia-Telangiectasia (Keimling_2011, Micol_2011, Mitui_2005, Sandoval_1999, Teraoka_1999). These data indicate that the variant is very likely to be associated with disease. One publication reported the complete absence of ATM protein (analyzed by western blotting) in a lymphoblastoid cell line (LCL) derived from a patient who was compound heterozygote for this variant and another truncating ATM variant (Keimling_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Thr1029Asnfs*19) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia telangiectasia (PMID: 9443866, 9887333, 10330348, 16266405, 29665859). This variant is also known as 3084insA, 3085insA, 3085_3086insA. ClinVar contains an entry for this variant (Variation ID: 230318). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:3
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in the heterozygous state in a patient with breast cancer (PMID: 29665859); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 9887333, 9443866, 10330348, 16266405, 30612635, 37149759, 29665859) -
ATM: PVS1, PM2, PS4:Moderate -
- -
Hereditary cancer-predisposing syndrome Pathogenic:3
This variant inserts 1 nucleotide in exon 21 of the ATM gene (also known as 3084insA, 3085insA, 3085_3086insA), creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 9443866, 16266405, 10330348, 9887333). Additionally, it has been reported in an individual affected with breast cancer (PMID: 29665859) and an individual affected with anaplastic astrocytoma (PMID: 37149759). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
The c.3085dupA pathogenic mutation, located in coding exon 20 of the ATM gene, results from a duplication of A at nucleotide position 3085, causing a translational frameshift with a predicted alternate stop codon (p.T1029Nfs*19). This mutation (also designated as c.3085_3086insA) has been reported in numerous individuals with Ataxia-Telangiectasia (A-T) (Telatar M et al. Am. J. Hum. Genet. 1998 Jan; 62(1):86-97; Teraoka S et al. Am. J. Hum. Genet. 1999 Jun; 64(6):1617-31; Sandoval N et al. Hum. Mol. Genet. 1999 Jan; 8(1):69-79; Mitui M et al. Ann. Hum. Genet. 2005 Nov; 69(Pt 6):657-64). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
ACMG/AMP, PVS1, PM2, PP5 -
Familial cancer of breast Pathogenic:2
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
- -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
- -
ATM-related disorder Pathogenic:1
The ATM c.3085dupA variant is predicted to result in a frameshift and premature protein termination (p.Thr1029Asnfs*19). This variant has been reported in individuals with ataxia telangiectasia (Table 2, referred to as c.3084insA, Telatar et al. 1998. PubMed ID: 9443866; Table 1, Sandoval et al. 1999. PubMed ID: 9887333; Table 2, Teraoka et al. 1999. PubMed ID: 10330348; Mitui et al. 2005. PubMed ID: 16266405; Table E1, Micol et al. 2011. PubMed ID: 21665257;). It has also been reported in an individual with breast cancer (Table 1, Renault et al. 2018. PubMed ID: 29665859). In vitro experimental studies indicate this variant impairs protein expression (Figure 1 and Table 1, Keimling et al. 2011. PubMed ID: 21778326). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/230318/). This variant is interpreted pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at